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Working Group 2: Lung Morphogenesis

Head: Robbert Rottier, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

The airways of Drosophila are very simply structured. Irrespective of the developmental stage each type of branching consists of a single layer of epithelial cells that just wrap around the airway space. Since in the fly’s airways interstitial cells, smooth muscle cells and as well as innate and adaptive immune cells are missing, Drosophila is suggested to be a highly attractive model to study airway epithelial maturation, organisation, and immunity exclusively in-vivo.

This WG aims to systematically describe the proteins involved in the cellular events of airway maturation and reveal their organization principles including control of physiological and pathological reactions. Understanding lung maturation at the molecular level in flies and mice can help to elucidate the control mechanisms of epithelial cell activities in vivo and provide a solid ground for identifying the causes of the complex pathologies of CLD.

In first instance, the following complementary strategies are be pursued:

  1. High-resolution, live-imaging methodologies to construct cell specific regulatory networks in the airways of Drosophila larvae. This construction of the networks will be based on detailed phenotypic classification using inert markers and the protein interaction partners from a recently completed genome-wide, tissue-specific screen for genes involved in airway maturation in Drosophila. A similar approach has the potential to be expanded to the mouse system.
  2. Transcriptional profiling of purified lung epithelial cell types to generate a comprehensive picture of the dynamic gene expression changes during lung maturation in mice. These experiments will determine molecular pathways to be assessed by statistical procedures for enrichment of conserved genes for even weak association with CLD pathology in GWAS studies.
  3. Evaluation of genetic risk factors implicated in chronic lung disease through GWAS in humans for involvement in lung maturation in the model systems. This bedside to bench approach ensures that all possible pathways relating to human CLD are evaluated.
  4. Genetic and biochemical characterization of conserved, uncharacterized components of airway maturation and chronic lung disease from 2, 3 and 4. These experiments will be performed in Drosophila, mice, and human samples building on established genetic tools.
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